Methods of making collagen fiber medical constructs and related medical constructs, including nerve guides and patches

ABSTRACT

The disclosure describes methods of winding collagen fiber to make medical constructs and related collagen fiber tube and patch devices.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 61/103,995 filed Oct. 9, 2008, and U.S. ProvisionalApplication Ser. No. 61/138,165 filed Dec. 17, 2008, the contents ofwhich are hereby incorporated by reference as if recited in full herein.

FIELD OF THE INVENTION

The invention relates to biomedical materials and products.

BACKGROUND OF THE INVENTION

Koob et al. have described methods of producing nordihydroguaiareticacid (NDGA) polymerized collagen fibers for various biomedicalapplications, some with tensile strengths similar to that of naturaltendon (e.g., about 91 MPa). See, for example, Koob and Hernandez,Material properties of polymerized NDGA-collagen composite fibers:development of biologically based tendon constructs, Biomaterials 2002Jan.; 23 (1): 203-12; and U.S. Pat. No. 6,565,960, the contents of whichare hereby incorporated by reference as if recited in full herein.

SUMMARY OF EMBODIMENTS OF THE INVENTION

Embodiments of the present invention are directed to methods of makingcollagen constructs for medical use and related constructs.

Particular embodiments are directed to nerve guides having a tube with awall having at least three laminated layers, including an intermediatelayer of at least one collagen fiber arranged in a repeating patternsandwiched by a collagen film outer surface and a collagen film innersurface.

The collagen film can be applied as a collagen gel to and the tube canbe cross-linked with nordihydroguaiaretic acid (NDGA) to create apolymerized collagen tube.

Some embodiments are directed to methods of manufacturing a medicalconstruct. The methods can include winding at least one collagen fiber anumber of revolutions about a length of a support member having a longaxis, the winding can have at least one defined pitch and/or fiber anglerelative to the long axis of the support member to form the construct.

The method may include placing a liquid or gel comprising solublecollagen onto the at least one wound collagen fiber during or after thewinding step so that the elongate construct is wetted and/or so that theouter surface is covered in a collagen film, when the soluble collagenis dry.

The method may also optionally include providing a spooled supply of atleast one collagen fiber for the winding step. The at least one collagenfiber may optionally be introduced to the support member from thespooled supply in a substantially dry state.

The winding step may be carried out to create multiple adjacentoverlying layers of the at least one fiber, the adjacent layers beingcoextensive for at least a major portion of a length of the construct.The pitches on the different layers on some portion of each layer maydiffer. For example, the winding step can be carried out to have a firstpitch for the winding of the at least one collagen fiber on the firstlayer and a second smaller or greater pitch for the winding of the atleast one collagen fiber on the second layer.

In some particular embodiments, the at least one fiber on the secondlayer resides between gaps defined by the at least one fiber wound withthe defined pitch on the first layer.

The method may include placing collagen gel about an outer surface ofthe support member before the winding step and allowing the collagen gelto dry to form a film on the support member. Then, the collagen fiberwinding can be carried out while applying soluble collagen to a surfaceof the at least one fiber on the support member. The wound collagenfiber with the soluble collagen is actively or passively dried, then acollagen gel can be applied over the dried collagen fiber with thesoluble collagen and, again allowed to dry, to form an outer layer offilm.

Other embodiments are directed to medical devices. The devices may be amaterial, an implant themselves or on or in implants. For example, thedevices can include a tube with a wall surrounding an axially extendingcavity. The wall has at least one collagen fiber (typically of acontinuous length of fiber) having a number of revolutions over at leasta major length of the tube with a pattern of intersecting segments. Thetube may also optionally have an inner layer of a collagen film and/oran outer layer of collagen film, each integrally attached to the atleast one collagen fiber.

The at least one collagen fiber can be derived from soluble dermalcollagen, and wherein the collagen film comprises soluble dermalcollagen having a collagen concentration of between about 0.1-4% weightper volume.

Particular embodiments are directed to nerve guides. The nerve guidesinclude a tube with a wall surrounding an axially extending cavity, thewall having at least one wound collagen fiber arranged with a number ofrevolutions over at least a major length of the tube on at least onelayer. Optionally, the nerve guide can include an inner layer of acollagen film and/or an outer layer of collagen film which may beintegrally attached to the collagen fiber.

The medical nerve guide or cuff can include an elastic tube with a wallsurrounding an axially extending cavity. The wall can have at least onecollagen fiber of a continuous length arranged in a fiber mesh patternof intersecting segments over at least a major length of the tube. Theat least one collagen fiber can be embedded in a collagen film thatextends over interstitial spaces defined by the fiber mesh pattern.

Other embodiments are directed to medical patches. The patches have atleast one collagen fiber having a length arranged in an angular patternwith adjacent layers defining fiber orientations that intersect. Thepatches may optionally have an inner layer of a collagen film and/or anouter layer of collagen film.

It is noted that aspects of the invention described with respect to oneembodiment, may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. Applicant reserves the right to change any originally filedclaim or file any new claim accordingly, including the right to be ableto amend any originally filed claim to depend from and/or incorporateany feature of any other claim although not originally claimed in thatmanner. These and other objects and/or aspects of the present inventionare explained in detail in the specification set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic cross-section (in an axial direction) of anexemplary collagen fiber construct on an exemplary support memberaccording to embodiments of the present invention.

FIG. 1B is an end view of the device shown in FIG. 1A (shown without thesupport member) according to embodiments of the present invention.

FIGS. 2A-2D are digital photographs of a prototype of a collagen fiberconstruct that may be particularly suitable for a nerve guide accordingto embodiments of the present invention.

FIG. 3A is a top perspective view of a lathe that can be used to windcollagen fiber(s) onto a tubular support member according to embodimentsof the present invention.

FIG. 3B is a side perspective view of the device shown in FIG. 3A.

FIG. 3C is a side perspective view of the lathe with a substantiallyplanar elongate support member according to embodiments of the presentinvention.

FIG. 3D is a side perspective view of a planar support member with awound collagen fiber(s) according to other embodiments of the presentinvention.

FIG. 3E is a side perspective view of a tubular support member with aninsert according to embodiments of the present invention.

FIG. 4 is a schematic illustration of different collagen fiberconfigurations that may be used for winding a construct according toembodiments of the present invention.

FIG. 5A is a schematic illustration of a tubular construct with segmentshaving increased fiber density according to embodiments of the presentinvention.

FIG. 5B is a schematic illustration showing that the tubular structureof FIG. 5A can be separated or cut into multiple different components(shown as two) according to embodiments of the present invention.

FIG. 6A is a schematic illustration of a substantially planar constructwith segments having increased fiber density according to embodiments ofthe present invention.

FIG. 6B is a schematic illustration of the construct shown in FIG. 6Aillustrating that the construct can be separated into multiplecomponents (shown as four) according to embodiments of the presentinvention.

FIG. 7 is a front view of a winding apparatus that can be used to wind(braid) collagen fiber according to embodiments of the presentinvention.

FIG. 8A is a schematic illustration of a collagen nerve guide accordingto embodiments of the present invention.

FIG. 8B is a schematic illustration of a collagen cuff according toembodiments of the present invention.

FIG. 9 is a schematic illustration of a medical kit according toembodiments of the present invention.

FIG. 10 is a flow chart of operations that can be used to fabricate aconstruct according to embodiments of the present invention.

FIG. 11 is a flow chart of an exemplary winding protocol according toparticular embodiments of the present invention.

DETAILED DESCRIPTION

The present invention now is described more fully hereinafter withreference to the accompanying drawings, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein; rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Like numbers refer to like elements throughout. In the figures, thethickness of certain lines, layers, components, elements or features maybe exaggerated for clarity. Broken lines illustrate optional features oroperations unless specified otherwise.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof. As used herein, the term “and/or”includes any and all combinations of one or more of the associatedlisted items. As used herein, phrases such as “between X and Y” and“between about X and Y” should be interpreted to include X and Y. Asused herein, phrases such as “between about X and Y” mean “between aboutX and about Y.” As used herein, phrases such as “from about X to Y” mean“from about X to about Y.”

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on”,“attached” to, “connected” to, “coupled” with, “contacting”, etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on”, “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

It will be understood that, although the terms first, second, etc. maybe used herein to describe various elements, components, regions, layersand/or sections, these elements, components, regions, layers and/orsections should not be limited by these terms. These terms are only usedto distinguish one element, component, region, layer or section fromanother region, layer or section. Thus, a first element, component,region, layer or section discussed below could be termed a secondelement, component, region, layer or section without departing from theteachings of the present invention. The sequence of operations (orsteps) is not limited to the order presented in the claims or figuresunless specifically indicated otherwise.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

The term “patch” refers to a piece or segment of biomaterial that can beplaced on and/or affixed to target anatomical structure, typically softtissue, to treat, protect, repair and/or reinforce a target site. Thepatch can be any geometric shape but is typically substantially planarand may, in position, conform to the shape of underlying or overlyingtissue.

The term “implantable” and derivatives thereof means the device can beinserted, embedded, grafted or otherwise acutely or chronically attachedor placed in or on a patient. The term “construct” refers to a deviceand/or material in a final form for use or in a pre-final form. The termpitch” means winding or wound at an angle relative to a first planenormal to the longitudinal axis of a core or cavity.

The terms “winding” and “wound” and derivatives thereof means to wrapabout an object or center at least once, typically repeatedly, e.g., toturn in a series of circular motions. In some embodiments, at least onecollagen fiber (multiple fibers, one or more fiber bundles) turns orrotates its circumferential position about a centerline or long axis.The winding may define a coil (e.g., a series of connected typicallysubstantially concentric rings or spirals), woven and/or braided fiberarrangement with a number of revolutions or turns about a core and/ortube, typically in a regular pattern (but an irregular pattern may alsobe used) about a length of at least one layer of a tube or cylindricalshape.

Embodiments of the present invention comprise collagen, typically dermalcollagen. However, the collagen can be of any form and from any origin.The collagen can be any of the identified collagen genotypes, forexample, the interstitial fiber forming collagen types I, II and III, aswell as any other substantially fiber forming types of collagen, forexample collagen VI. The collagen can be acid soluble collagen or pepsinsolubilized or soluble collagen. The collagen can be from mammaliancells synthesized in vitro. The collagen can be from molecularlyengineered constructs and synthesized by bacterial, yeast or any othermolecularly manipulated cell type. For example, the collagen can be seacucumber dermis collagen, bovine, caprine, porcine, ovine or othersuitable donor mammal, marine animal collagen such as chinoderms,molecularly engineered collagen, or gelatin (e.g., in any suitable formincluding solid, gel, hydrogels, liquids, or foams). In addition, thecollagen can be digested with a protease before, where used, oxidizingand polymerizing steps. The collagen can be in the form of microfibrils,fibrils, natural fibers, or synthetic fibers.

In some embodiments, the collagen can be solubilized, dissolved orotherwise transferred into an acid solution, for example, acetic acid(e.g., about 0.01M to about 1.0M, typically about 0.5M), hydrochloricacid (between about pH 1 to about pH 3, typically about pH 2.0), or anyother suitable acid at appropriate concentration (e.g., about pH 1.0 toabout pH 3.0, typically about pH 2.0). Dialysis may optionally be usedto neutralize a soluble collagen solution. The collagen can also oralternatively be dissolved in a neutral buffered solution either with orwithout salts, e.g., phosphate buffer at about pH 7.0, or phosphatebuffered saline at about pH 7.0. The phosphate buffer can be at anyconcentration of sodium phosphate between about 0.01 and 0.5, but moretypically between about 0.02 and about 0.1M. The buffer can also be anybuffer, including, but not limited to, for example, sodium acetate,HEPES, or MOPS. The collagen can be present in a quantity that is atleast about 0.1% to about 10%, typically between 0,1% to about 5% (e.g.,about 0.1, 0.2, 0.3, 0.4, 1.0, 2.0, 4.0%) by weight per volume, or byweight per volume in the neutral buffer solution before fibrillogenesisand fiber formation. In a dried fiber collagen, collagen can be presentin an amount of weight by volume of between about 50-100% (e.g., atleast about 75%, 90%, 95% or 100%) before crosslinking (wherecrosslinking is used).

Collagen “microfibrils,” “fibrils,” “fibers,” and “natural fibers” referto naturally-occurring structures found in a tendon. Microfibrils areabout 3.5 to 50 nm in diameter. Fibrils are about 50 nm to 50 μm indiameter. Natural fibers are above 50 μm in diameter. A “syntheticfiber” refers to any fiber-like material that has been formed and/orchemically or physically created or altered from its naturally-occurringstate. For example, an extruded fiber of fibrils formed from a digestedtendon is a synthetic fiber but a tendon fiber newly harvested from amammal is a natural fiber.

Of course, synthetic collagen fibers can include non-collagenouscomponents or biocompatible materials, such as particulates,hydroxyapatite and other mineral phases, or drugs that facilitate tissuegrowth or other desired effects. See, U.S. Pat. No. 6,821,530,incorporated herein by reference above. For example, the fibers and/orconstructs formed from same, can include compositions that can containcarbon nano-tubes, zinc nano-wires, nano-crystalline diamond, or othernano-scale particulates; and larger crystalline and non-crystallineparticulates such as calcium phosphate, calcium sulfate, apatiteminerals. For example, the compositions can also or alternativelycontain therapeutic agents such as bisphosphonates, anti-inflammatorysteroids, growth factors such as basic fibroblast growth factor, tumorgrowth factor beta, bone morphogenic proteins, platelet-derived growthfactor, and insulin-like growth factors; chemotactic factors suchfibronectin and hyaluronan; and extracellular matrix molecules such asaggrecan, biglycan, decorin, fibromodulin, COMP, elastin, and fibrillin.In some embodiments, the fibers and/or fiber-derived constructs cancontain cells, engineered cells, stem cells, and the like. Combinationsof the above or other materials can be embedded, coated and/or otherwisedirectly or indirectly attached to the collagen fibers and/or constructformed of same.

The term “collagen gel” means a semi-solid (e.g., gelatinous density)material that includes collagen fiber, fibrils and/or microfibrils,typically dermal collagen, that has been acid or pepsin solubilized(e.g., soluble collagen) and processed to maintain the collagen in itsmolecular form. The collagen concentration of the soluble collagenand/or resulting soluble collagen gel can be between about 0.1% to about4% weight per volume. The soluble collagen gel may be formed to be in acylindrical shape of a defined length and diameter, typically with adiameter of between about 0.1 to 1 cm, and a length of between about 5cm to about 100 m, more typically between about 1 m to about 50 m.

The collagen fibers and collagen gel can be produced in batch orcontinuous-type systems, including wet gel collagen extrusion systems,which produce cylindrical lengths of gel that can be allowed tosubstantially dry (actively or passively) to obtain a suitable length offiber. Examples of some collagen fiber production processes that cangenerate soluble collagen in suitable lengths are described in U.S. Pat.No. 6,565,960, and pending U.S. Patent Application Publication No.US-2008-0188933-A1, the contents of which are hereby incorporated byreference.

The collagen fibers can be spooled for supplying to an automated orsemi-automated winder to form the biomedical construct. The collagenfibers may be formed with a relatively thin diameter, such as, forexample between about 0.05 mm to about 0.2 mm (average), such as about0.08 mm dry diameter (average) and about a 0.13 mm wet diameter(average).

The term “film” refers to a thin layer of collagen gel that has dried.The film is typically present in a thickness that is between about 5 and200 microns. The film may be permeable and flexible and opticallytransmissive, e.g., translucent or transparent, or may be opaque.Several layers of the gel can be applied to generate the desired filmthickness or coverage. The color or transmissve characteristics maychange when hydrated. The film can infuse into, migrate and/or bond to acoiled or wound (dry) collagen fiber to form a collagen fiber laminate.The gel/film is not required, but where used can provide a smooth (andtypically a substantially constant diameter) surface over or under thefiber.

Referring now to the figures, FIG. 1A, an exemplary elongate construct10 is shown on a support member 20. As shown, the construct 10 includesan inner layer of collagen film 11, an intermediate layer of at leastone wound collagen Fiber 13, and an outer layer of collagen film 15.

In other embodiments, the construct 10 can be formed without the innerand/or outer layer of film 11 and/or may optionally include othermaterials or constituents and/or layers. For example, hydroxyapatite canbe placed into the collagen fiber and/or collagen gel material. Thisconfiguration can be particularly suitable to augment interference screwfixation of autograft tendons.

As shown in FIG. 1B, the construct 10 can have a wall 10 w with asuitable thickness defined by the at least one collagen fiber 13 and thefilm layers (where used) and/or other coatings and/or materials placedthereon. The construct 10 can have an open through cavity or may befilled or partially filled with a nerve-growth media or othertherapeutic material (e.g., an anti-inflammatory, antibiotic and/or thelike).

As also shown, the at least one collagen fiber 13 has an angular fiberpattern 13 p of repeating intersecting collagen fiber segments along itslength. The angular pattern 13 p can be defined by a number ofrevolutions of the at least one fiber 13 about the support member 20 ata given pitch or pitches for at least one layer (typically more than onelayer). The support member 20 is used to wrap the at least one collagenfiber around its exterior surface to form a desired shape. The supportmember 20 can include a lubricious and/or smooth surface, or an embossedsurface with lower contact surface area, typically of a polymermaterial. In other embodiments, the support member 20 can include ananti-slip surface with ridges or a sleeve can be placed over the supportmember (not shown) to contact the next layer (e.g., inner film 11 orfiber 13). In some embodiments, the support member 20 comprises Teflon®or other suitable low friction and/or anti-stick material. The supportmember 20 can be tubular, e.g., cylindrical, as shown in FIGS. 1A, 3A,3B and 3E or may be substantially flat and rectangular 20′ as shown inFIGS. 3C and 3D. Other geometries may also be used, such as, forexample, a frustoconical or funnel shape. Typically, the support member20 is elongate and has a substantially circular, oval, polygonal orother cross-sectional shape.

The at least one collagen fiber 13 can be organized into various arraysincluding braids, weaves, knits, parallel arrays, and various patterns.The orientation of one or more of the fibers 13 within the resultingmaterial 10 (see, e.g., FIGS. 2A-2D) can be targeted to meet thespecific mechanical requirements of the medical application. Fiberdensity can vary from dense to loose geometries and the numbers and sizeof the one or more collagen fibers used can vary as well as thethickness of the film to provide specific mechanical properties. Thefiber(s) 13 can be continuous length fibers or may be formed byattaching a series of collagen fibers in an end-to-end orientation 13 j(FIG. 4).

FIGS. 2A-21) are digital photographs of a prototype of a construct 10.This construct 10 may be particularly suitable as a nerve tube or guide10 n (FIG. 8A). The construct 10 is tubular 10 t with an open cavity andhas a flexible elastic configuration. The construct 10 may be configuredas a nerve guide 10 n. The nerve guide 10 n can be formed using a singlefiber 13 formed in wound multiple layers, the fiber 13 can have a lengthbetween about 1-6 m, typically about 5 m. The nerve guide 10 n can beformed using a single fiber 13 of a continuous length that is wrapped inseveral layers about the support member 20. Use of a single fiber 13 canreduce the likelihood of any fraying associated with multiple fibers(such as those wound in one lengthwise direction). The nerve guide 10 ncan have a length between about 1 cm to about 6 cm (or more), and theinner diameter can be between about 1-10 m with the wall thickness beingabout 0.1 mm to about 3 mm.

The construct 10 can have reversible elasticity with sufficient rigidityor strength to prevent undue nerve compression, while allowingflexibility sufficient to allow the construct 10 to spring back into itsoriginal shape after being exposed to a strain or tension caused bynormal body movement that deforms the shape. The nerve guide 10 n can beused for any nerve location, e.g., peripheral nerves (such as in a handor finger), spinal cord nerves, and the like. The construct 10 can beused for other repairs or treatments as will be discussed further below.The construct 10 is biocompatible (or at least non-cytotoxic) and canprovide a desired half-life suitable for its intended function.

The construct 10 and/or the fiber 13 can be cross-linked with a suitablepolymerizing material, such as, but not limited to, NDGA, or may be usedin a non-cross-linked state. The NDGA cross-linking can increase thestrength of the device 10 but may decrease the resiliency, elasticity orflexibility. In some embodiments, the collagen fiber 13 is notcross-linked during the winding process, but may optionally becross-linked after the winding process (typically after the collagenfilm has been applied to the outer surface and dried).

The support member 20 can be configured to facilitate removal of theconstruct 10. For example, the construct 10 may be wound tightly againstthe outer surface of the support member 20 and allowed to dry. Thesupport member 20 can be configured to reduce in cross-sectional size ordisassemble with the construct 10 held thereon to allow easy removal ofthe elongate construct. In some embodiments, the support member 20 canbe a multi-piece device that provides this size change. In otherembodiments, the support member 20 may be cooled while the construct isheated to provide a size difference. In particular embodiments, thesupport member 20 can cooperate with an insert 20I (FIG. 3D) thatprovides the desired size adjustability. In other embodiments, theconstruct 10 can be removed from the support member without such a sizeadjustment (e.g., its inner surface may be sufficiently lubricous or asuitable liquid or other material can be used to slide the construct offthe support member. In other embodiments, the construct 10 can be cut ina lengthwise (e.g., “X”) direction and taken off the support member 20.In some embodiments, the construct 10 may be cut or otherwise separatedin a long axis direction with a longitudinal slit 10 s and used for acuff 10 e (FIG. 8B) that can be positioned about a nerve or other tissueto protect that tissue (and the cuff may be sutured together along atleast a portion of the long axis and/or may be sutured or otherwiseanchored into position). The cuff 10 c may be configured to provide asnug or alternatively, a non-constricting, encasement for injuredperipheral nerves for protection of the neural environment. The wall ofthe cuff with the longitudinal slit 10 s can be spread open for easyplacement over the injured nerve or other target tissue. The resilienceof the collagen conduit allows the cuff to recover and maintain closureonce the device is placed around the nerve.

As shown in FIGS. 3A-3B, the construct 10 can be made by winding atleast one collagen fiber 13 around a support member 20 using acomputer-guided and/or controlled lathe system 100. The lathe system canbe configured to rotate the support member 20 and to move the supportmember back and forth in a length direction to alter the location of thefiber on the support member 20 relative to the introduction point of thefiber (e.g., the fiber introduction point may be stationary). In otherembodiments, the fiber(s) 13 can be supplied through a head that movesrelative to the support member 20 (e.g., the support member can bestationary) or both the fiber introduction head and the support membermay move relative to teach other.

Different size (e.g., diameter) support members 20 can be used dependingon the target product. For example, transverse small cross-sectionsupport members (e.g., diameter rods) can be used for manufacturingdevices for use in vein and artery replacements or repairs, while largertransverse cross-section support members (e.g. diameter rods) can beused to manufacture devices for aortic or large artery replacements orrepairs and/or various shunts.

An example of a small lathe 100, typically a micro or miniature lathe,suitable for fabricating embodiments of the constructs is the Model 4410lathe available from Sherline Products, Inc., having a place of businessin Vista, Calif. Two user-selectable inputs can operate the lathesystem: one controls the speed that the support member that spins andthe other controls the pattern (fiber angle) in which the at least onefiber 13 is laid onto the support member. The operation can beconfigured so that the fiber is self-pulling from a spool incommunication with a channel in the feeder head based on the speed ofthe spinning support member 20. The lathe 100 can co-wind a plurality offibers or fiber bundles substantially concurrently about the supportmember 20.

The at least one collagen fiber 13 can be coated with one or more layersof collagen gel 11, 15 and/or other suitable bio-compatible materialduring and/or after winding the at least one collagen fiber 13 to sealthe fiber(s) 13 within the biocomposite material and/or to form a smoothinner and/or outer surface of the construct 10. FIG. 3B illustrates thatcollagen gel can be applied to the fiber 13 on the support member duringthe winding. FIG. 3B illustrates that a brush 111 can be used to applythe gel. Other application techniques may be used, such as spray, pour,drop, and the like. The application of the soluble collage gel may bemanual or automated and applied by electro-mechanical devices.

The winding can be performed so that at least one layer of the at leastone collagen fiber has a substantially constant pitch for at least amajor portion of a length thereof or so that at least one layer of theat least one collagen fiber has a variable pitch for at least a majorportion of a length thereof.

FIG. 4 illustrates that different configurations of fibers 13 may beused. Examples of fiber configurations include a single fiber 13 ₁, aplurality of fibers 13 ₁-13 n (typically n=2 to 100) that can beconcurrently co-wound about the support member 20, a fiber bundle 13 b,and a twisted, woven or braided fiber bundle 13 t. For the fiber bundles13 b, 13 t, two or more fibers 13 can be grouped together to form thefiber bundle 13 b, 13 t and that bundle 13 b, 13 t applied or wrappedabout the support member 20, similar to a single fiber. One or morefiber bundles 13 b, 13 t may be used to form the construct 10.Combinations of the different fiber types may also be used for someconstructs 10. That is, for example, a twisted fiber 13 t can beco-wound with a single fiber 13 ₁ and/or a single fiber 13 ₁ may be usedto form one layer and a twisted 13 t to form a different layer, and thelike.

The collagen fiber 13 can be wound using various fiber angles (e.g.,pitch angles), such as, angles between about 2-70 degrees, typicallybetween about 5-60 degrees, such as, for example, 5, 10, 15, 20, 25, 30,35, 40, 45, 50, 54 and 55 degrees, or other odd or even numbers between5-70. Where constructs of multiple layers are used, one layer may have afirst pitch and another layer may have a different pitch.

FIG. 5A illustrates that a construct 10 can be wound with increasedfiber density 52 along certain segments, typically forming end rings 52r. This increased fiber density 52 can provide sufficient rigidity toallow a suture to attach thereto. As shown in FIG. 5A, the construct 10is tubular 10 t and may optionally include an increased density segment52 at an intermediate location. FIG. 5B illustrates that the construct10 can be used as formed, or may be cut or separated along a Y-axis intotwo components 10 ta, 10 tb. For the latter, the intermediate increaseddensity ring 52 can form end rings for the separated construct 10 ta, 10tb.

FIG. 6A illustrates a construct 10 that is relatively flat 10 f and/orrectangular. Again, the construct 10 f can optionally include increasedfiber density segments 52 that may be suitable for end rings 52 r. FIG.6 illustrates that the construct 10 f can be cut along the X-axis andseparated into at least two components that form biocompatible patches.The intermediate increased density ring(s) 52, where used, canoptionally form end rings 52 for the separated construct 10 fa, 10 fb,etc.

FIG. 7 illustrates an example of another automated winding system 100′that can be used to form the construct 10. This embodiment uses severalfibers 13, each independently wound and/or wrapped to weave or braid thefibers about the support member 20 to form the construct 10. The system100′ includes a plate 122 supporting spindles 124, a forming plate 126,a support member (shown as a cylindrical mandrel) 20 that extendsthrough an aperture in the fainting plate 126, and braid puller 128. Anexemplary microbraider is believed to be available from Kokubun Ltd ofJapan. See also, FIG. 2 and col. 2 of U.S. Pat. No. 7,135,040, thecontent of which is hereby incorporated by reference.

The fibers 13 can be wound before or after cross-linking (or notcross-linked at all). If wound before, the fibers can, where desired, bepolymerized with any suitable cross-linking materials, to promotecollagen organization, such as, for example, NDGA, but othercross-linking materials may be used, including, for example,glutaraldehyde. The (dried) collagen fiber can also be treated withother methods to improve the tensile properties of the fiber. The(dried) collagen fibers 13 can be cross-linked with agents such asglutaraldehyde, formaldehyde, epoxy resins, tannic acid, or any otherchemical agent that produces covalent cross-links between collagenmolecules within fibrils or between fibrils. Alternatively, the fiber 13can be treated to induce cross-linking between collagen molecules suchas, but not limited to, one or more of a carbodiimide treatment,ultraviolet irradiation either with or without carbohydrates to initiateglycation adducts, and dehydrothermal treatment coupled with any of theaforementioned methods.

FIG. 9 illustrates a medical kit 250 that includes a medical device orimplant 10 or 10′. The kit 250 may optionally include other components,such as, for example, a container of surgical adhesive, sutures 210,suture anchors, and the like. The device or implant 10, 10′ may be heldhydrated in a flexible sealed package of sterile liquid 230. The kit 250may include a temperature warning so that the construct 10, 10′ is notexposed to unduly hot temperatures that may degrade the implant. Atemperature sensor 252 may optionally be included on the package of thekit to alert the clinician as to any excessive or undue temperatureexposure prior to implantation. For example, it may be desirable to holdor store the kit 250 (and implant or device 10, 10′) at a temperaturethat is less than about 37° C. and/or 100° F. prior to implantation. Thekit 250 may be packaged in a housing with a temperature controlled orinsulated chamber 250 e to facilitate an appropriate temperature range.

FIG. 10 is a flow chart of operations that can be used to carry outembodiments of the present invention. In some embodiments, the at leastone collagen fiber is wound a number of revolutions about a length of asupport member having a long axis. The winding can have a defined pitchand/or fiber angle relative to the long axis of the support member toform an elongate construct with at least one wound collagen fiber (block150). The winding step can form multiple overlying layers of the atleast one collagen fiber in one or more fiber angles so that the atleast one fiber intersects itself at different locations along a lengthof the construct.

Optionally, a collagen gel can be placed onto the support member and thegel can dry to form a film on the outer surface of the support memberbefore the winding step (block 155). The collagen film can be dried orallowed to dry on the support member (e.g., rod). As the fiber(s) iswound about the support member, a soluble collagen can be applied (e.g.,wrapped, painted, sprayed, dripped and the like) onto the fiber(s)and/or support member so that the fiber(s) become wet while one or morelayers are wound on the lathe.

The at least one collagen fiber can be supplied to the winder/supportmember in a substantially dry state and may be provided as a spooled(dry) quantity of the at least one collagen fiber (block 152). Thefiber(s) can be supplied and wound in a non-cross-linked state.

In some embodiments, the winding step can be carried out to createmultiple adjacent overlying layers of the at least one fiber, theadjacent layers being coextensive for at least a major portion of alength of the construct (block 153). A liquid or gel comprising solublecollagen can be placed onto the at least one wound collagen fiber tocover at least the outer surface in a collagen film (block 165).

Optionally, the placing of the collagen gel or liquid is carried out byplacing collagen gel having a cylindrical shape around the at least onewound collagen fiber and the support member (block 158).

Optionally, the collagen can be polymerized while the elongate constructis held on the support member using a suitable cross-linker, such as,for example, NDGA, then removing the construct from the support member(block 166).

The winding can be carried out so that the at least one fiber turnsabout the support member in one of a clockwise or counterclockwisedirection along a first lengthwise direction for a first layer, thenreverses to travel in an opposing lengthwise direction and continues toturn about the support member in the same clockwise or counterclockwisedirection for a second adjacent layer (block 180, FIG. 11).Alternatively, in particular embodiments, the winding may be carried outso that the at least one collagen fiber turns (is wrapped) about thesupport member in one of a clockwise or counterclockwise direction alonga first lengthwise direction for a first layer, then reverses to travelin an opposing lengthwise direction and turns about the support memberin the other clockwise or counterclockwise direction a second adjacentlayer.

In some embodiments, the winding step has a first pitch for the windingof the at least one collagen fiber on the first layer and a secondsmaller or greater pitch for the winding of the at least one collagenfiber on the second layer. In some embodiments, the at least one fiberon the second layer resides between gaps defined by the at least onefiber wound with the defined pitch on the first layer.

The method can include cutting the construct in an axial direction toform a flat collagen fiber patch. The method can include winding thecollagen fibers in a plurality of axially spaced apart segments withincreased collagen fiber density, at least some of which are provided asreinforced segments for suturing. The reinforced segments can be formedat end portions of the tube and optionally at one or more intermediatelocations therebetween. The methods can produce a nerve guide havingsufficient strength and elasticity to withstand buckling and to be ableto bend and to elastically return to its original shape after bending toinhibit occlusive pressures or restrictions on nerves.

Embodiments of the invention can be used for a number of differentmedical applications, including, but not limited to, nerve guides, woundbed patches, muscle or organ patches, cardiac patches, valvereplacements or repairs, hernia patches, skin patches, burn treatmentpatches, skin/tissue repair patches or cuffs, blood vessel (artery,vein, and the like) repairs, sleeves that can reside about repairingtendon to prevent or inhibit adhesions, indwelling tubes for delivery oftherapeutic agents, ducts such as lymphatic, hepatic, pancreatic andcystic ducts, tubes such as ureter and urethra tubes and the like.

The present invention is explained in greater detail in the followingnon-limiting Examples.

Example

FIGS. 2A-2D illustrate exemplary sleeves or tubes of wound NDGA-collagenfibers that may be particularly suitable for nerve guides. The innerdiameter of the tube can vary between about 1 and 10 mm. The thicknessof the wall can vary between about 0.1 and 3 mm. The length of the tubecan vary from between about 1 to 6 cm or more.

The tube can be made of dermal collagen that is acid or pepsin soluble.The soluble collagen can be made by neutralizing acid soluble collagenand keeping the soluble collagen at a desired low temperature tomaintain the collagen in molecular form, (e.g., about 4° C.). Collagengels can be produced from acid soluble collagen by neutralization,injection molding in a Teflon® tube of diameter between 0.1 cm to 1.0 cmand incubation for at least about 4 hours at 37° C. The resulting gelcan be extruded into deionized water to form a gel cylinder with adiameter between about 0.1 cm to 1.0 cm (and can have a length betweenabout 1-100 m. Collagen concentration of the soluble collagen andcollagen gel can be from about 0.1-4% weight per volume. The gelcylinder can be used in the gel form or allowed to dry, actively orpassively (suspended in air), to form a collagen fiber having a diameterbetween about 0.05 mm (average) to about 0.2 mm (average).

The first step to make this prototype tube is to wrap the collagen gelof specified collagen concentration and diameter onto a Teflon® rod ofselected diameter. The collagen gel layer was allowed to dry on the rodat room temperature to form a thin layer of collagen film. The thicknessof this collagen film can be varied by applying more or less layers ofcollagen gel, either is a single application of in several applications.

The second step is to wind dry collagen fibers on to the collagen filmcoated Teflon® rod. The pitch of the fiber relative to the long axis ofthe tube can be specified. The thickness of the collagen winding can beadjusted, for example, corresponding to the number of layers of fibersthat are laid on (and/or the number of fibers bundled together for thewinding). During the fiber winding process, soluble collagen is applied(e.g., painted) onto the surface of the laid-on fibers. The thickness ofthe final soluble collagen layer can be varied to achieve specificthickness. The soluble collagen coated fiber wound cylinder is allowedto dry.

The third step in making the tube is the same as the first step, e.g.,to wrap a collagen gel on to the collagen fiber would Teflon® rod andthe gel layer is allowed to dry to form a collagen film enwrapping thecollagen fiber tube. The thickness of the penultimate collagen film canbe varied by the number of layers of wrapped gel.

The dried tube can be used “as-is” (used in a non-cross-linked state andhydrated when in the body or prior to placement in the body), or it canbe cross-linked with any agent or action that cross-links the collagen.The (nerve) tube is then taken off the Teflon® rod. In the presentexample, the tube is cross-linked with nor-dihydroguaiaretic acid(NDGA), see, e.g., U.S. Pat. No. 6,565,960, and U.S. Patent ApplicationPublication No. US-2008-0161917-A1, the contents of which are herebyincorporated by reference as if recited in full herein.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. The invention is defined by the following claims, withequivalents of the claims to be included therein.

1. A method of manufacturing a medical construct, comprising: winding at least one collagen fiber a number of revolutions about a length of a support member having a long axis, the winding having at least one defined pitch and/or fiber angle relative to the long axis of the support member to form the construct.
 2. A method according to claim 1, further comprising placing a liquid or gel comprising soluble collagen onto the at least one wound collagen fiber during or after the winding step so that the construct is wetted and/or so that the outer surface is covered in a collagen film when the soluble collagen is dry.
 3. A method according to claim 1, further comprising providing a spooled supply of a continuous length of the at least one collagen fiber that is between about 1 m to about 100 m for the winding step.
 4. A method according to claim 3, wherein the at least one collagen fiber is introduced to the support member from the spooled supply in a substantially dry state.
 5. A method according to claim 1, wherein the winding step is carried out to create multiple adjacent overlying layers of the at least one fiber, the adjacent layers being coextensive for at least a major portion of a length of the construct.
 6. A method according to claim 1, wherein the at least one collagen fiber comprises at least one fiber that has a length that is formed by connecting a series of collagen fibers in an end-to-end orientation.
 7. A method according to claim 5, wherein the winding is carried out so that the at least one fiber turns about the support member in one of a clockwise or counterclockwise direction along a first lengthwise direction for a first layer, then reverses direction and turns about the support member in the other clockwise or counterclockwise direction in an opposing lengthwise direction for a second adjacent layer.
 8. A method according to claim 1, wherein the support member has a longitudinal axis, and wherein the winding step winds a continuous length of at least one collagen fiber at a first pitch on a first layer and winds a continuous length of the at least one collagen fiber at a second smaller or greater pitch for a second layer.
 9. A method according to claim 8, wherein the at least one collagen fiber on the second layer resides between gaps defined by the at least one collagen fiber wound with the first pitch on the first layer.
 10. A method according to claim 1, further comprising placing a gel of soluble collagen having a substantially cylindrical shape on the support member before the winding step, and placing a gel of soluble collagen over the at least one fiber after and/or during the winding step.
 11. A method according to claim 1, wherein the support member is substantially cylindrical.
 12. A method according to claim 1, wherein the support member is substantially rectangular.
 13. A method according to claim 1, further comprising: placing collagen gel about an outer surface of the support member before the winding step; and allowing the collagen gel to dry to form a film on the support member before the winding step; then winding the at least one collagen fiber about the support member over the film while applying a liquid and/or gel of soluble collagen to a surface of the at least one fiber on the support member; and allowing the wound collagen fiber with the soluble collagen to dry; then applying a collagen gel over the dried collagen fiber with the soluble collagen and allowing the applied collagen to dry to form an outer layer of film.
 14. A method according to claim 2, further comprising, after the placing of the soluble collagen on the at least one wound collagen fiber, allowing the fiber and collagen to dry, then polymerizing the collagen while the construct is held on the support member using NDGA cross-linking, then removing the support member.
 15. A method according to claim 1, wherein the winding step is carried out using a lathe to automatically wind the at least one collagen fiber about the support member at a desired fiber angle and at a desired rotating speed of the support member.
 16. A method according to claim 1, further comprising cutting the construct in an axial direction to form a substantially flat collagen fiber patch.
 17. A method according to claim 1, further comprising winding the collagen fibers in a plurality of axially spaced apart segments with increased collagen fiber density, at least some of which are provided as reinforced segments for suturing.
 18. A method according to claim 17, wherein the reinforced segments are formed at end portions of the tube.
 19. A method according to claim 17, wherein the reinforced segments are formed at end portions of the tube and at least one intermediate location therebetween.
 20. A method according to claim 1, wherein the construct is a nerve cuff, and wherein the at least one collagen fiber is a single collagen fiber that is wound in a first axial direction relative to the support member for a length of the construct then wound in a second opposing axial direction relative to the support member for a length of the tube thereby providing an anti-fray configuration for the nerve cuff.
 21. A method according to claim 1, wherein the at least one collagen fiber is a single fiber that is wound in a first axial direction for a length of the tube, then wound in a second opposing axial direction for a length of the tube to form multiple overlying layers of the single collagen fiber, and wherein collagen film resides on the inner and outer surfaces of the construct and defines a smooth inner surface and smooth outer surface.
 22. A method according to claim 1, wherein the at least one collagen fiber includes at least one collagen fiber bundle.
 23. A method according to claim 13, wherein the at least one collagen fiber is a single fiber bundle.
 24. A method according to claim 1, wherein the winding step is carried out to form multiple overlying layers of the at least one collagen fiber in one or more fiber angles so that the at least one fiber intersects itself at different locations along a length of the construct.
 25. A method according to claim 1, wherein the at least one collagen fiber is a plurality of fibers, wherein the winding step comprises winding the plurality of fibers substantially concurrently about the support member.
 26. A method according to claim 13, wherein the at least one collagen fiber is a plurality of multiple-fiber bundles, wherein the winding step comprises winding the plurality of fibers substantially concurrently about the support member.
 27. A method according to claim 1, wherein the winding step is carried out so that the at least one fiber is wound at a substantially constant pitch for at least a major portion of a length thereof.
 28. A method according to claim 1, wherein the winding step is carried out so that the winding of at least one layer of the at least one collagen fiber has a varying pitch over a length thereof.
 29. A method according to claim 2, wherein the soluble collagen is an extruded gel of soluble collagen having a collagen concentration of between about 0.1% to about 4% weight per volume, and wherein the collagen fiber (dry) has a diameter of between about 0.05 mm to about 0.2 mm (average).
 30. A method according to claim 1, wherein the at least one collagen fiber is uncross-linked during the winding step.
 31. A method according to claim 1, wherein the at least one collagen fiber is cross-linked with NDGA before the winding step.
 32. A method according to claim 1, further comprising removing the support member after cross-linking the collagen while the wound fiber is held on the support member.
 33. A method according to claim 1, wherein the construct is a nerve guide, and wherein the nerve guide has sufficient strength and elasticity to, in use, withstand buckling and to be able to bend and to elastically return to its original shape after bending to inhibit occlusive pressures or restrictions on a nerve.
 34. A medical device, comprising: a tube with a wall surrounding an axially extending cavity, the wall having an at least one collagen fiber, the fiber having a length arranged in a pattern of overlying intersecting segments over at least a major length of the tube.
 35. A medical device according to claim 34, wherein the at least one collagen fiber is derived from extruded soluble dermal collagen, and wherein the collagen film comprises soluble dermal collagen having a collagen concentration of between about 0.1-4% weight per volume.
 36. A medical device according to claim 34, wherein the collagen film and collagen fiber are cross-linked with NDGA.
 37. A medical device according to claim 34, wherein the at least one collagen fiber comprises a first fiber layer of a continuous wound length of at least one collagen fiber extending about a core or cavity at an angle of between about 0° to 90° relative to a first plane normal to a longitudinal axis of the tube.
 38. A medical device according to claim 37, wherein the at least one collagen fiber comprises a second fiber layer with the at least one collagen fiber extending about the longitudinal axis of the tube at an angle of between about 5° to 55° relative to the first plane normal to the longitudinal axis.
 39. A medical device according to claim 34, wherein the medical device is a nerve guide or nerve cuff.
 40. A medical device according to claim 34, wherein the at least one collagen fiber is a single collagen fiber arranged in multiple stacked wound layers, the single fiber having a continuous length with a diameter when dry of between about 0.05 mm (average) to about 0.2 mm (average).
 41. A medical device according to claim 34, further comprising an inner layer of a collagen film attached to the at least one collagen fiber defining an inner surface of the tube wall and an outer layer of collagen film attached to the at least one collagen fiber defining an outer surface of the tube wall.
 42. A medical patch comprising at least one collagen fiber arranged in an angular pattern of a plurality of adjacent layers, with a first layer has a first fiber orientation and a second layer has a second fiber orientation arranged so that the first and second fiber orientations intersect.
 43. A medical patch according to claim 42, further comprising an inner layer of a collagen film and an outer layer of collagen film.
 44. A medical patch according to claim 42, wherein the patch is implantable or the patch is an external patch for a wound closure or treating a burn.
 45. A medical patch according to claim 42, wherein the patch comprises a greater density of fibers on end portions thereof.
 46. A medical patch according to claim 41, wherein the collagen is cross-linked with NDGA.
 47. A medical patch according to claim 42, further comprising an inner layer of collagen film residing under the adjacent layers and an outer layer of collagen film residing over the adjacent layers.
 48. A medical nerve guide or cuff, comprising: a tube with a wall surrounding an axially extending cavity, the wall having at least one wound collagen fiber arranged with a number of revolutions over at least a major length of the tube on at least one layer; an inner layer of a collagen film attached to the at least one collagen fiber defining an inner surface of the wall; and an outer layer of collagen film integrally attached to the at least one collagen fiber defining an outer surface of the wall.
 49. A nerve guide or cuff according to claim 48, wherein the tube is elastic with sufficient rigidity to be able to elastically deform when exposed to normal bending while providing resistance against nerve compression, then return to an original length and configuration when the bending force is removed or reduced.
 50. A nerve guide or cuff according to claim 48, wherein the at least one collagen fiber is a soluble dermal collagen fiber, wherein the collagen film comprises soluble dermal collagen having a collagen concentration of between about 0.1-4% weight per volume.
 51. A nerve guide or cuff according to claim 48, wherein the collagen film and collagen fiber are derived from soluble dermal collagen, and wherein the collagen film and fiber are cross-linked with NDGA.
 52. A nerve guide or cuff according to claim 48, wherein the at least one collagen fiber is a single collagen fiber having a diameter between about 0.05 mm to about 0.2 mm (average, dry) arranged in multiple stacked layers of coils, and wherein the wall thickness is between about 1 and 10 mm, and the tube has a length that is between about 1-6 cm.
 53. A nerve guide or cuff according to claim 48, wherein the tube wall comprises a longitudinally extending slit.
 54. A medical nerve guide or cuff, comprising: an elastic tube with a wall surrounding an axially extending cavity, the wall having at least one collagen fiber of a continuous length arranged in a fiber mesh pattern of overlying intersecting segments over at least a major length of the tube, the at least one collagen fiber embedded in a collagen film that extends over interstitial spaces defined by the fiber mesh pattern.
 55. A medical nerve guide or cuff according to claim 54, wherein the tube wall comprises a longitudinally extending slit. 